Transglutaminase 2 mediates hypoxia-induced selective mRNA translation via polyamination of 4EBPs

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Hypoxia, low oxygen, paradoxically enhances mRNA translation in cancer cells, aiding metastasis and survival, despite suppressed mTORC1 activity.
• The precise mechanisms governing this selective translation under hypoxia remain largely unknown.
• Understanding this process is crucial for developing targeted cancer therapies.

Purpose of the Study:

• To elucidate the novel pathway linking hypoxia to selective mRNA translation.
• To identify key molecular players involved in hypoxia-induced translational control.
• To explore transglutaminase 2 (TG2) as a potential therapeutic target in cancer.

Main Methods:

• Investigated the role of hypoxia-inducible factor 1 (HIF-1) and its target enzyme, transglutaminase 2 (TG2).
• Examined the polyamination of eukaryotic translation initiation factor 4E (eIF4E)-binding proteins (4EBPs) by TG2 under hypoxic conditions.
• Utilized proteomic analyses to identify specific mRNA subsets translationally regulated by TG2.

Main Results:

• TG2, induced by hypoxia, polyaminates 4EBPs, enhancing their phosphorylation and promoting cap-dependent translation.
• TG2 activity preferentially boosts translation of mRNAs with G/C-rich 5'UTRs, excluding those with upstream ORFs or TOP motifs.
• Identified TG2 as a critical regulator of hypoxia-driven selective mRNA translation.

Conclusions:

• TG2 acts as a key mediator in the paradoxical enhancement of mRNA translation during hypoxia in cancer cells.
• The TG2-mediated pathway provides a novel mechanism for cancer cell adaptation and progression.
• TG2 represents a promising molecular target for anti-cancer therapeutic strategies.